The development of non-invasive imaging procedures that provide surrogate markers for prognosis and early response to therapy has the potential to improve clinicians' ability to effectively treat patients with oncologic disease. However, the incorporation of advanced imaging into oncology research settings has been slowed by a lack of adequate informatics technology. The Integrative Imaging Informatics for Cancer Research (I3CR) program will address this gap informatics technology by developing two informatics platforms. The I3CR Data Management Platform will serve as an informatics hub that integrates image acquisition, analysis workflows, phenotypic and genomic data sources, and clinical information and treatment systems. The Data Management Platform will be developed as a major new extension of the XNAT imaging informatics system to include additional cancer-specific data types, new web services, support for a number of widely used data formats, and customized user interface components. In addition, I3CR will collaborate with a number of external technology providers to integrate the Data Management Platform with widely used visualization and analysis applications, complementary database systems, and clinical diagnostic and treatment systems. The I3CR Knowledge Management Platform will enable researchers to publish portfolios that document and track the source data, derived data, software applications and scripts, and computing resources used to generate scientific findings. The Knowledge Management Platform will integrate seamlessly with widely used workflow engines and the Data Management Platform to generate knowledge portfolios that can be tied directly to publications to enable reproducible research. The central hypothesis of the I3CR program is that integrative informatics technology will enable cancer researchers to overcome technical hurdles that currently impede scientific progress. We will evaluate this hypothesis within the context of a federated network of cancer imaging researchers, including members of the NCI Quantitative Imaging Network that will undertake pilot projects in radiation therapy dose optimization and glioblastoma tumor mapping. All software will be open source and supported through a number of outreach channels, including annual technical workshops, monthly teleconferences, and an active web-based discussion forum.